N-(alkoxyalkyl)-4, 7-diamino-2-aryl-6-pteridinecarboxamides



United States Patent 3,122,543 N-{ALKGXYALKYD4,7-DlAllWG-LARYL-6- PTEFEENECAlEQXH/EEES Thomas S. Qsdene, West Chester, Pa, assignor to American Home Products Corporation, New Jerk, N.Y., a

er-oran'on of Delaware No Dravrlng. lied July 2, E62, Ser. No. 207,098 5 Claims. (J3 ass-251.5

This invention relates to novel pteridine compounds possessing useful pharmacological properties. More particularly, it relates to alkoxyalkylamides of 4,7-d1amino- 2-aryl-6-pteridinecarbox lic acids. The compounds of this invention have the formula wiere Ar represents an aryl group which may be phenyl or phenyl substituted once or twice by lower alkyl, lower allzoxy, fluorine, chlorine, bromine, or triiluorornethyl substituents, R represents hydrogen or lower alkyl, alk represents an alkylene radical containing from one to four carbon atoms (e.g., methylene, ethylene, trimethylene, or tetrarnethylene), and R represents a lower alkyl group.

As used herein, the terms lower alkyl and lower alkoxy signify alkyl and alkoxy groups containing from one to four carbon atoms.

These novel pteridine derivatives exhibit diuretic activity, especially in a triuretic activity, and are also anti-viral and anti-bacterial agents. By reason of these useful properties, coupled with their very low toxicities, the compounds of this invention are of value in both human and veterinary medicine.

Several processes are suitable for preparing the compounds of this invention. A particularly preferred process comprises heating together in an anhydrous neutral polar solvent a 4,6-diamino-2-aryl-5-nitrosopyrimidine and an N-alkoxyalliyl cyanoacetamide in the presence of a basic catalyst, whereby a condensation reaction is effected according to the following equation.

Particularly suitable neutral polar solvents for this reac tion are alcohols such as methanol, ethanol, propanol, and butanol, glycol others such as Z-methoxyethanol, 2- ethoxyethanol, and methoxy and ethoxy propanols, and amides such as dirnethylforrnarnide, diethylformarnide, and dirnethylacetamide. Suitable basic catalysts for promoting the above condensation reaction include the alkdl metal alkoxides and the alkali metal allsoxyalkoxides such as sodium methoxide, potassium ethoxide, sodium Z-methoxyethoxide, and sodium Z-ethoxyethoxide. Reaction temperatures of about 60 to 260 C. are suitable, and the reaction is ordinarily substantially complete in less than an hours heating at such temperatures.

The novel pteridines of this invention may also be prepared by several processes in which a 4,7-diamino2- arylpteridine substituted in the 6-position by a carboxy, carbamido, carboallzoxy, or cyano radical is then trans- 3,122,543 Patented Feb. 25, 1964 "ice 2 formed into one of the l -(allroxyalkyl)-6-pteridinecarboxarnides of the invention.

Thus, for example, a 4,6-diamino-Z-aryl-5-nitroso pyrimidine may be condensed with an alkyl cyanoacetate (by heating in anhydrous ethanol in the presence of sodium ethoxide, for example) to yield a 6-carboalkoXy-4,7- diarnino-2-arylpteridine. Such an ester may be reacted with an alkoxyalkyl amine of the formula (wherein R, alk, and R have the meanings previously given) to form an i -(alkoxyalkyl)-4,7-diamino-2-aryl- 6-pteridinecarboxarnide of this invention.

An alternative method of preparation is to react a 6- carboalkoxyt-J-diamino-Z arylpteridine with an alkanolamine of formula (wherein R and alk have the meanings previously given) to form an N (hydroxyalkyl) 4,7 diamino 2 aryl-6- pteridinecarboxamide which may then be converted by warming with thionyl chloride to an N-(chloroalkyl)-4,7- diarnino-2-aryl-6-pteridinecarboxamide which, by reaction with an alkali metal all (oxide, is converted to an N-(alkoxyalkyl)-4,7-diamino-2--aryl-fi-pteridinecarboxamide of this invention.

A generally less satisfactory but operable variant of the preceding method comprises treating a -carboalkoxy- 4,7-diamino-2-arylpteridine with a haloalkylamine such as one having the formula HNRalk-Cl (in which R and all: have the meanings previously given) and then treating the resulting N-(haloalkyl)-4,7-diamino-2-aryl- 6-pteridinecarboxamide with a sodium alkoxide to yield an N- alkoxyalicyl -4,7-diamino-2-aryl-6-pteridinecarboxamide of this invention.

Instead of preforming a -carboalkoxy-4,7-diamino-2- arylpteridine and thereafter operating to replace the alk- OXY radical thereof by an alkoxyamide radical, as just described, one may prepare a 4,7-diaznino-2-aryl-6- pteridinecarboxylic acid by condensing a 4,6-dia1nino-2- aryl :i-nitrosopyrimidine with cyanoacetic acid; this pteridinecarboxylic acid may be converted to an acid chloride by treatment with thionyl chloride, phosphorus trichclo ride, phosphoryl chloride, or phosphorus pentachloride, and then condensed with an alkoxyalkanolamine to yield an N-(allioxyalkyl)-4,7-diamino-2-aryl-6-pteridinecarboxamide of this invention. The 4,7-diamino-2-aryl-6-pteridinecarboxylic acid chloride may, of course, be reacted with an alkanolamine to form an N-(hydroXyalkyl)-4,7- diamino-Z-aryl-6-pteridinecarboxamide which can be treated with thionyl chloride to replace the hydroxyl group by chlorine which may then in turn be replaced by alkoxy by treatment with an alkali metal alkoxide.

Another possible variation comprises esterifying a 4,7- diamino-Z-aryl-S-pteridinecarboxylic acid by any suitable means and thereafter reacting the resulting ester with an allioxyalltylarnine as above or with a hydroxyalkylamine or haloalliylamine and then following the already outlined reaction sequences to obatin the N-(alkoxyalkyl)- 4,7-diarnino-Z-aryl-S-pteridinecarboxamides of this invention.

A still further route to the compounds of this invention is one in which a 4,6-diamino-Z-aryl-S-nitrosopyrimidine is condensed with malononitrile to form the corresponding 4,7-diamino-2-aryl-6-cyanopteridine, and in wl ich this cyanoptericline is subsequently reacted with hydrogen chloride and a lower alkanol to form an iminoether. Such an iminoether may then be treated with an alkoxyallcylamine or an hydroxyalkylamine to form an amidine which is hydrolyzed to yield an N-(alkoxyallc'l)-4,7-diarnino2-aryl-6-pteridinecarboxamide of this invention or an N-(hydroxyallryl)-4,7-diamino-2- aryl-6-pteridinecarboxamide which by the reactions discussed above may be converted to an N-(alkoxyalkyl)- 4,7-diarnino-2-aryl-6pterldinecarboxamide of this invention.

The following examples illustrate the preparation of these new pteridine compounds. Examples l3 show the preparation of typical cyanoacetamides of value as intermediates in this invention, and Examples 41O show how pteridines typical of this invention may be prepared.

Example 1 Example 2 A mixture of 44.6 g. of Z-ethoxyethylamine, 56.5 g. of ethyl cyanoacetate and 100 ml. of absolute ethanol is boiled under reflux for 2 hours and 40 minutes. After removal or" the solvent on a rotary evaporator, the residual gum is scratched and solidifies. Recrystallization from ethyl acetate and petroleum ether ailords 2-cyano-N-(2- ethoxyethyl)acetamide, M.P. 45 C.

Analysis-Calculated: C=53.83, H=7.74, N=17.94. Found: C=53.70, 111:7.73, N=17.82.

Example 3 A mixture of 75 g. of Z-methoxyethylamine, 113 g. of ethyl cyanoacetate and 100 ml. of absolute ethanol is boiled under reflux for 2 /2 hours. After concentration of the solution on a rotary evaporator the residual gum is cooled and the mass crystallizes. Recrystallization from ethyl acetate yields 2-cyano-N-(Z-methoxyethyl)acetamide, M.P. 79 C.

Analysis.Calculated: C=50.69, H=7.09, N =19.7l. Found C=50.71, H=7.02, N=19.86.

Example 4 To a solution of 0.2 g. of sodium metal in 500 ml. of absolute ethanol is added 6.45 g. of 4,6-diamino-2-phenyl- S-nitrosopyrimidine, and the mixture is stirred and heated to the boiling point. This is followed by the addition of 6.0 g. of Z-cyano-N-(3-isopropoxypropyl)acetamide and the whole is boiled under reflux for 30 minutes. Concentration of the solution to small bulk yields a solid, wt.=9.1 g., M.P. 269270 C. Recrystallization from ethanol yields 4,7-diamino-N-(3-isopropoxypropyl)-2- phenyl-6-pteridinecarboxamide, M.P. 265 C.

Example 5 i To a solution of 0.2 g. of sodium metal in 400 ml. of absolute ethanol is added 6.45 g. of 4,6-diamin-2-phenyl- S-nitrosopyrimidine; the mixture is stirred mechanically and boiled under reflux for minutes. Following this, 5.15 g. of 2-cyano-N-(Z-ethoxyethyl)acetamide is added and boiling continued for 1 hour. On cooling, the solution deposits crystals of N-(Z-ethoxyethyl)-4,7-diamino-2- phenyl-6-pteridinecarboxarnide, wt.=7.3 g., M.P. 283 C. Recrystallization from ethanol affords a product melting at 282 C.

Analysis.-Calculated: C=57.78, H=5.42, N=27.75. Found: C=57.99, H=5.76, N=28.01.

Example 6 To a solution of 0.2 g. of sodium metal in 400 ml. of absolute ethanol is added 6.45 g. of 4,6-diamino-2-phenyl- S-nitrosopyrimidine, followed by 4.7 g. of Z-cyano-N-(L methoxyethyl)acetamide. The mixture is stirred and boiled under reflux for 1 hour. On cooling, yellow crystals are deposited, wt.=7.8 g., M.P. 294 C. Recrystalli zation from aqueous 2-ethoxyethanol aifords N-(2-metl1 oxyethyl) 4,7 diamino 2 phenyl 6-pteridinecarboxamide, M.P. 293 C.

Analysis.-Calculated: C=56.63, H=5.05, N=28.90. Found: C=S6.32, H=4.91, N:28.6l.

Example 7 To a solution of 0.2 g. of sodium in 500 ml. of absolute ethanol is added 5.68 g. of 4,6-diamino-2-(3,4-dichlorophenyl)-5-nitrosopyrimidine, followed by 3.5 g. of 2- cyano N (2 ethoxyethyDacetamide. The mixture is stirred and boiled under reflux for 30 minutes, during which time a yellow crystalline material deposits out of solution. After cooling, this is removed by filtration and recrystallized from ethanol to yield N-(2-ethoxyethyl)- 4,7 diamino 2 (3,4 dichlorophenyl) 6 pteridinecarboxamide, M.P. 285 C.

Analysis.- Calculated: C=48.35, H=4.06, N=23.22, Cl=16.79. Found: C=48.58, H=3.97, N=23.33, Cl=16.77.

Example 8 N (2 methoxyethyl) 4,7 diamino 2 (p ChlOl'O,

phenyl)-6-pteridinecarboxamide is prepared by the reaction of 4,6 diamino 2 (p chlorophenyl) S-nitrosopyrimidine with Z-cyano-N-(Z-methoxyethyl)acetamide as in Example 6.

Example 9 N (3 isopropoxypropyl) 4,7 diamino 2 (ptolyl)-6-pteridinecarboxamide is prepared by the reaction of 4,6 diamino 2 (p tolyl) 5 nitrosopyrimidine with 2 cyano N (3 isopropoxypropyl)acetamide as in Example 4.

Example 10 N (2 ethoxyethyl) 4,7 diamino 2 (p anisyl)- 6-pteridinecarboxamide is prepared by the reaction of 4,6- diamin0-2-(p-anisyl)-5-nitrosopyrimidine with Z-cyano-N- (Z-ethoxyethyl)-acetamide as in Example 5.

Example 11 N (2 methoxyethyl) 4,7 diamino 2- (o tolyl)- 6-pteridinecarboxamide is prepared by the reaction of 4,6- diamino-Z-(o-tolyl)-5-nitrosopyrimidine with Z-cyano-N- (Z-methoxyethyl)acetamide as in Example 6.

I claim:

1. The compound of the formula:

wherein: Ar is a member selected from the group consisting of phenyl and phenyl substituted by from one to two members of the group consisting of lower alkyl, lower alkoxy, fluorine, chlorine, bromine, and trifluoromethyl; R is a member selected from the group consisting of hydrogen and lower alkyl; alk is a member selected from the group consisting of methylene, ethylene, trirnethylene and tetramethylene and R is lower alkyl.

2. N (3 isopropoxypropyl) 4,7 diamino 2- phenyl-6-pteridinecarboxamide.

3. N (2 ethoxyethyl) 4,7 diamino 2 phenyl 6- pteridinecarboxamide.

4. N (2 methoxyethyl) 4,7 diamino 2 phenyl- 6-pt ridinecarboxamide.

5. N (2 ethoxyethyl) 4,7 diamino 2 (3,4 dichlorophenyl) 6 pteridinecarboxamide.

References Cited in the file of this patent UNITED STATES PATENTS 2,975,180 Osdene Mar. 14, 1961 

1. THE COMPOUND OF THE FORMULA: 